The goals of the SCOR in thrombosis are to elucidate and characterize basic mechanisms and pathways involved in the pathogenesis of thrombosis at the molecular cell biological, and genetic levels, to identify and clone new cDNA molecules encoding components of the thrombotic/hemostatic mechanism, and to develop the means to modify and prevent thrombotic disease and its consequences in man. The specific aims of the proposal include: a) the characterization of novel phospholipids and their pathway of metabolism in platelets and NIH 3T3 cells; b) the physiological significance of cyclic inositol phosphates in signal transduction; c) the role of autocrine mechanisms of growth factor/growth factor receptor interactions in cell proliferation; d) elucidation of a newly discovered growth factor, namely heparin binding growth factor 8 (HBGF-8); e) investigation of the structure/function relationships of heparin co-factor II, thrombomodulin, and thrombospondin; f) population study and identification of mutations in heparin co-factor II, factor VII, factor X, and anti-thrombin III; g) determination of functional dermatan sulfate oligosaccharide catalyzing heparin co-factor II reactions; h) definition of transcriptional control of human tissue factor synthesis and degradation; i) definition of the role of thrombospondin in its anti-angiogenic action; j) determination of the role of factor XIa inhibitor in hemostasis, thrombosis, and Alzheimer disease; k) determination of potential new pathway for activation of factor XI. The methods to be utilized include: a) protein purification, identification, and characterization; b) mutagenesis, cloning, and expression of cDNA constructs; c) cell biological technology, immunological and immunochemical techniques; d) identification of novel inositol metabolites involved in cell signalling by enzymology and HPLC chromatography. Multiple collaborative investigations both within the SCOR and with other SCOR programs are ongoing and will be developed further. Internal coordination of programs and extensive external and internal review processes will continue. Conferences and relevant courses will be use to disseminate results and to interest new investigators in the field of thrombosis. The SCOR program thus plans a highly integrated and directed effort to further understand thrombotic disease and to develop means for effective diagnoses and therapy.